Extended characterisation of the serotonin 2A (5-HT 2A) receptor-selective PET radiotracer 11C-MDL100907 in humans: Quantitative analysis, test-retest reproducibility, and vulnerability to endogenous 5-HT tone

INTRODUCTION: scanning properties and analytic methodology of the 5-HT(2A) receptor-selective positron emission tomography (PET) tracer (11)C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects. METHODS: 64 (11)C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18–55 yr). 12 subjects were scanned twice (duration 150 min) to provide data on plasma analysis, model order estimation, and stability and test-retest characteristics of outcome measures. All other scans were 90 min duration. 3 subjects completed scanning at baseline and following 5-HT(2A) receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyze the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT(2A) receptors. RESULTS: optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90 minutes achieved stable outcome measures in all cortical regions except orbitofrontal which required 120 minutes. Binding potential (BP(P) and BP(ND)) test-retest variability was very good (7–11%) in neocortical regions other than orbitofrontal, and moderately good (14–20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT(2A) receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6 µg to remain below 5% receptor occupancy. (11)C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BP(ND) were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalization. Mean age-related decline in brain 5-HT(2A) receptors was 14.0 ± 5.0% per decade, and higher in prefrontal regions. CONCLUSIONS: our data confirm and extend support for (11)C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT(2A) receptors in the human brain

Modulation of amphetamine-induced dopamine release by group II metabotropic glutamate receptor agonist LY354740 in non-human primates studied with positron emission tomography

Pharmacological evidence suggests that schizophrenia is associated with increased stimulation of dopamine (DA) D2 receptors. Recently, several groups have demonstrated that amphetamine-induced DA release is increased in schizophrenia, providing direct evidence for dysregulation of DA systems in this condition. In healthy volunteers, pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine increases amphetamine-induced DA release to levels similar to those observed in patients with schizophrenia. Therefore, the dysregulation of DA function observed in schizophrenia might be secondary to NMDA hypofunction. In this study, the regulation of this response by glutamate (GLU) transmission was further characterized by using a metabotropic glutamate (mGlu) receptor group II agonist to inhibit GLU transmission. The amphetamine- (0.5 mg/kg intravenously (i.v.)) induced decrease in [11C]raclopride equilibrium-specific binding (V3″) was measured under control conditions and following pretreatment with the mGlu2/3 receptor agonist LY354740 (20 mg/kg i.v.) in four baboons. Amphetamine reduced [11C]raclopride V3″ by 28 ± 7% under control conditions. Following LY354740 pretreatment, amphetamine-induced reduction in [11C]raclopride V3″ was significantly enhanced (35 ± 7%, p = 0.002). The enhancement of the amphetamine-induced reduction in [11C]raclopride V3″ by LY354740 was not a simple additive effect, as LY354740 alone did not reduce [11C]raclopride V3″. In conclusion, the results of this study further document the involvement of GLU transmission in regulating the effect of amphetamine-induced DA release, and provide additional support to the hypothesis that the dysregulation of DA function revealed by the amphetamine challenge in schizophrenia might stem from a deficit in GLU transmission